Quaternary ammonium compounds



United States Patent 2,903,464 QUATERNARY AMMONIUM COMPOUNDS Lincoln Harvey Werner, Summit, N.J., assignor to Ciba Pharmaceutical Products, Inc, Summit, N.J., a corporation of New Jersey No Drawing. Application October 24, 1956 Serial No.'617,914 I The present invention relates to a new series of quaternary ammonium compounds and process for making same. More particularly this invention is concerned with quaternary ammonium-lower alkyl-1,4-dioxane com-' wherein D stands for a 1,4-dioxane radical, A for a lower alkylene radical, and wherein R R and R when taken together with the nitrogen atom represent an N,N,N-trihydrocarbon-substituted amino group or an N- hydrocarbon substituted, partially or totally saturated nucleus containing at least one ring-secondary nitrogen atom as a ring member, or may form a partially or totally unsaturated nucleus containing at least one ring-tertiary nitrogen atom as a ring member and X stands for an anion. v

In the above formula D represents a 1,4-dioxane radi cal which may be unsubstituted or substituted. Thus, the 1,4-dioxane ring, for example, may be substituted with hydrocarbon radicals, more especially lower alkyl radicals having from 1 to ,7 carbon atoms, e.g. methyl ethyl, propyl, isopropyl or butyl; aryl groups, such as monoor bicyclic aryl groups, for example, substituted, e.g. halogenated, or more especially unsubstituted "phenyl radicals; or halogen atoms, e.g. chlorine or bromine. Further substituents of the 1,4-dioxane ring designed to enhance the pharmacological or physical, e.g. solubilizing properties of the compounds are, for example, amino, aminoalkyl, aminoalkylamino, aminoalkoxy, polyhydroxyalkyl, azaor oxaalkyl or hydroxy-oxaalkyl groups.

The lower alkylene group A in the above formula contains preferably from 1 to 3 carbon atomsand is primarily a methylene group which may be advantageously unsubstituted or may contain lower hydrocarbon radicals, such as, for example, lower alkyl radicals, e.g. methyl or ethyl. i

As outlined above, the nitrogen atom of the quaternary ammonium group of this invention may, when taken together with the substituents R R and R form an N,N,N-tri-hydrocarbon-substituted amino group or an N- hydrocarbon substituted, partially or totally, saturated nucleus containing at least one ring-secondary nitrogen atom or a partially or totally unsaturated nucleus containing at least one ring-tertiary nitrogen atom. Two valences of a ring-secondary nitrogen atom form part of the ring and three valences of a ring-tertiary nitrogen atom form part of the ring. Thus, in the above formula R R and R may be hydrocarbon radicals, such as saturated or unsaturated lower hydrocarbon radicals having from 1 to 7 carbon atoms, for example, lower alkyl, lower alkenyl or lower aralkyl radicals, e.g. methyl, ethyl, propyl, isopropyl, butyl, allyl or benzyl. An N- hydrocarbon substituted, partially or totally saturated nucleus containing at least one ringsecondary nitrogen atom is more especially an N-hydrocarbon substituted monoor bicyclic nucleus, the ring of which being, for example, an N,N-lower alkylene-amino residue containing in the ring from 4 to 6 carbon atoms, e.g. the pyrrolidino, piperidino, hexamethyleneamino, morpholino, thiomorpholino or piperazino radicals, or a partially saturated bicyclic residue, e.g. the 1,2,3,4-tetrahydroquinolino or -isoquinolino radicals. The hydrocarbon radical in such an N-hydrocarbon substituted, partially or totally saturated nucleus is primarily a saturated or unsaturated lower hydrocarbon radical having from 1 to 7 carbon atoms, for example, lower alkyl, lower alkenyl or lower aralkyl radicals, e.g. methyl, ethyl, propyl, isopropyl, butyl, allyl or benzyl. Thirdly, a partially or totally unsaturated nucleus containing at least one ringtertiary nitrogen atom is especially a monoor bicyclic ring system containing at most one ring-tertiary nitrogen atom as a ring member, such as, for example, the pyridine, quonoline, isoquinoline or 3,4-dihydro-isoquinoline nucleus.

The anion X in the above formula is more especially a therapeutically useful anion of an acid such as that of an inorganic acid, for example, of a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acids, sulfuric acid, phosphoric acid, nitric acid or thiocyanic acid; or an organic carboxylic acid, such as, for example, acetic, acetoacetic, propionic, B-cyclopentyl-propionic, oxalic, lnalonic, succinic, maleic, furnaric, malic, citric, tartaric, benzoic, phenylacetic, B-phenylpropionic, salicylic, acetylsalicylic or p-aminosalicylic acid; or of an organic sulfonic or sulfuric acid, such as, for example, p-toluene sulfonic acid, methane sulfonic acid, ethane sulfonic acid, or methyl or ethyl sulfuric acid half ester. The anion X may be also the hydroxyl ion.

The quaternary ammonium-lower alkyl-1,4-dioxane compounds of this invention show a parasympathomimetic action and can be used as cholinergic agents in medicaments, especially in ophthalmic preparations. A pronounced parasympathomimetic action is shown by quaternary ammonium-methyl-l,4-dioxane compounds of the formula:

R1 QB l e DCH2NR2 X l, in which D represents a 1,4-dioxane radical, R R and R represent lower hydrocarbon radicals containing from 1 to 7 carbon atoms or wherein R R and R when taken together with the nitrogen atom form an N-lower hydrocarbon substituted partially or totally saturated, especially monocyclic nucleus, the ring system of which contains in the ring from 4 to 6 carbon atoms, and the lower hydrocarbon radical contains from 1 to 7 carbon atoms, or wherein R R and R when taken together with the nitrogen atom stand for the pyridine, quinoline or isoquinoline nucleus, and wherein X represents a therapeutically useful anion of an acid or the hydroxyl ion. Very active with respect to the cholinergic action are N,N,N-tri-lower hydrocarbonor N-lower hydrocarbon-N,N-alkylene-ammonium-methyl 1,4 dioxane compounds, the hydrocarbon radicals of which contain from 1 to 7 carbon atoms, in which the 1,4-dioxane radical is unsubstituted or substituted by not more than two lower alkyl groups, e.g. methyl or ethyl, or by one or two phenyl groups, and in which the anion X represents a therapeutically useful anion of an acid or the hydroxyl ion. Of this group, the compounds of the formula:

at O -CH2NR2 x in which R R and R represent lower alkyl, lower alkenyl and lower aralkyl groups and wherein X stands for a therapeutically useful anion of an acid, or a hydroxyl ion, and more particularly compounds of the formula:

Q3 9 O CH2N(CH3)Z X wherein X stands for a bromine, iodine, hydroxyl and especially for a chlorine ion, show outstanding parasympathomimetic action.

The new compounds may be used as medicam'ents in the form of pharmaceutical preparations, which contain the new quaternary ammonium compounds in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, cholesterol or any other known carrier for medicaments. The pharmaceutical preparations may be, for example, in the form of tablets or dragees, or in liquid form as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or butters. Sterile ophthalmic preparations may, for example, contain from 0.01 to percent of the quaternary ammonium compound in standard isotonic and buffered aqueous solutions. They may also contain, in combination, other therapeutically useful substances.

I prepare the new quaternary ammonium lower alkylene 1,4-dioxane compounds according to known methods for the preparation of quaternary ammonium compounds. Generally, the process for the preparation of the new quaternary ammonium-lower alkylene-l,4-dioxane compounds consists in reacting suitably substituted tertiary amines with a reactive ester of an alcohol so as to produce the desired quaternary ammonium compound. Reactive esters of alcohols are especially those with strong inorganic or organic acids.

Thus, an amine of the formula:

wherein D stands for a 1,4-dioxane radical, A represents a lower alkylene, especially the methylene radical, and R and R stand for hydrocarbon radicals as outlined above or, when taken together with the nitrogen atom, are part of a partially or totally saturated ring system as mentioned above, may be reacted with the reactive ester of an alcohol R OH. R represents a hydrocarbon radical, especially a lower alkyl, lower alkenyl or lower aralkyl radical, such as, for example, methyl, ethyl, propyl, allyl or benzyl. Reactive esters of alcohols of the formula: R OH with strong acids are more especially those with strong inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic or hydriodic acid, or sulfuric acid; with strong organic sulfonic acids such as, for example, aryl sulfonic acids, e.g. ptoluene sulfonic acid, or alkyl sulfonic acids, e.g. methane sulfonic or ethane sulfonic acid; or with strong organic sulfuric acids, e.g. methyl or ethyl sulfuric acid half ester.

A second modification of the general process consists in reacting a reactive ester of a hydroxy-lower alkyl- 1,4-dioxane compound With a tertiary amine under formation of the quaternary ammonium-lower alkyl-1,4-dioxane compound. Reactive esters of a hydroxy-lower alkyl-1,4-dioxane are more especially those with strong inorganic or organic acids; such as outlined previously.

Tertiary amines which may be used are more especially amines of the formula:

R: Rr-IL-Ra in which R R and R when taken together with the nitrogen atom represent an N,N,N-tri-hydrocarbon substituted amine or may form an N-hydrocarbon-substituted, partially or totally saturated cyclic amine containing at least one ring-secondary nitrogen atom as a ring member, or may form a partially or totally unsaturated cyclic amine, containing at least one ring-tertiary nitrogen atom as a ring member. Apart from tertiary amines containing only one amino group there may be used tertiary amines containing more than one amino group, such as, for example, in a piperazino derivative, provided that the additional amino groups are protected, for example, are in the form of an amid grouping; in other words, such tertiary amines may contain acylated, such as acetylated, amino groups. Specific examples of the three types of amines suitable for this modification of the general process are, for example, tri-lower hydrocarbon amines, e.g. trimethylamine, triethylamine, ethyldimethylamine, diethyl-methylamine, dimethyl-allylamine, diallyl-methylamine, benZyl-dimethylamine or benzyl-diethylamine; N-lower hydrocarbon-substituted, partially or totally saturated heterocyclic nuclei, such as, for example, N-methyl-pyrrolidine, N-ethyl-pyrrolidine, N-allyl-pyrrolidine, N-benzyl-pyrrolidine, N-methyl-piperidine, N-ethyl-piperidine, N-benZyl-pyrrolidine, N-methyl-morpholine, N ethylmorpholine, N benzylmorpholine, N-methyl-thiomorpholine, N-methyl-hexamethyleneamine, N-methyl-N'-acetyl-piperazine, N-methyl-1,2,3,4-tetrahydroquinoline or N-methyl-1,2,3,4-tetrahyd'roisoquinoline; or partially or totally unsaturated heterocycles containing at least one ring-tertiary nitrogen atom as a ring member, preferably monoor bicyclic ring systems containing at most one ring-tertiary nitrogen atom as a ringmember, such as, for example, pyridine, quinoline, isoquinoline or 5,6,7,8 tetrahydroquinoline.

The quaternizing reactions, such as outlined above, are performed according to standard procedures, i.e. in the presence or absence of" a solvent, at room temperature or at an elevated temperature or under cooling, at atmospheric pressure or in a closed vessel under pressure. Suitable solvents are more especially alkanols, e.g. methanol, ethanol, propanol, isopropanol or amyl alcohol; or organic acid amides, e.g. formamide or dimethylformamide. When reactive esters of'hydroxylated lower hydrocarbon compounds are used as quaternizing agents, formamide and dimethylformamide are the preferred solvents and the reaction is advantageously run in a closed vessel under pressure, the latter being built up by heating.

Quaternary ammonium-lower alkyl-1,4-dioxane compounds. such as those obtained by'the process of the invention, may be converted into the corresponding quaternary ammonium hydroxides, for example, by reaction of the quaternary ammonium halides obtained by the process of the invention with silver oxide, or by reaction of the sulfates with barium hydroxide or by treating the quaternarysalts with an anion exchanger or by electrodialysis. From any resulting base there may be made therapeutically suitable quaternary ammonium salts by reaction with the acids, for example, with inorganic acids such as hydrohalic acids, e.g. hydrochloric, hydrobromic or hydriodic acid, sulfuric acid, phosphoric acids, nitric acid or thiocyanicacid; or organic acids, such as acetic, acetoacetic, propionic, ,B-cyclopentyl propionic, oxalic, malonic, succinic, maleic, fumaric, malic, citric, tartaric, benzoic, phenylacetic, p-phenylpropionic, salicylic, acetylsalicylic or p-aminosalicylic acid, p-toluenesulfonic, methane sulfonic. or ethane sulfonic acid or dimethyl or diethyl sulfate. The quaternary ammonium salts obtained may also be converted into other quaternary salts directly without conversion into the quaternary hydroxide, for

ALA

example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride.

The starting materials, insofar as they are new, are prepared according to known methods. Thus, reactive esters of hydroxy-methyl-l,4-dioxane compounds, for example, may be conveniently prepared according to the general method given by L. H. Werner and C. R. Scholz, -J. Amer. Chem. Soc, vol. 76, p. 2701 (1954). Starting materials which may be used in the preparation of the quaternary ammonium-lower alkyl-1,4-dioxane compounds of the general formula depicted above, in which the alkylene radical A is, for example, a methylene group substituted by a lower hydrocarbon radical, e.g. a methyl :group, may be prepared according to the general procedure outlined by L. H. Werner and C. R. Scholz, c. cit., by using a fl-allyloxy-ethanol derivative containing a lower hydrocarbon radical, e.g. a methyl group, in the 3- jPOSlfiOll of the allyl group, for the ring closure step to the 1,4-dioxane ring. ,B-Allyloxy-ethanols, in which the :allyl radical contains a lower hydrocarbon radical, e.g. a methyl group, in the 2-position, may also be used in the cyclyzation according to L. H. Werner and C. R. Scholz; tthe 1,4-dioxane compounds thus-obtained show a lower hydrocarbon substituent, e.g. a methyl group, in the 2- position of the ring.

The following examples are intended to illustrate the invention. They are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 87.2 g. of iodomethyl-1,4-dioxane is dissolved in 160 ml. of ethanol, 100 g. of trimethylamine are added to this solution and the reaction mixture is heated in a pressure vessel to 80 to 100 for four hours. On cooling the product crystallizes, is filtered off, washed with ethanol and recrystallized from the same solvent. 69.6 g. of trimethyl-ammonium-methyl-1,4-dioxane iodide of M.P. 206- 210" are obtained.

'The trimethyl ammonium-methyl-1,4-dioxane obtained may be converted into the d-tartrate by shaking an aqueous solution thereof with an aqueous solution of a small excess of silver oxide. After filtration of the silver iodide precipitate, the aqueous filtrate is treated with an aqueous solution of an excess of d-tartaric acid. After concentration under reduced pressure the trimethyl-ammoniummethyl-1,4-dioxane d-tartrate can be isolated.

Instead of d-tartaric acid other acids may be used to form quaternary ammonium salts, such as, inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, thiocyanic acid; or organic acids, e.g. such as acetic, acetoacetic, propionic, p-cyclopentyl propionic, oxalic, malonic, succinic, maleic, fumaric, malic, citric, benzoic, phenylacetic, fl-phenylpropionic, salicylic, acetylsalicylic or p-aminosalicylic acid, p-toluenesulfonic, methane sulfonic or ethane sulfonic acid, or dimethyl or diethyl sulfate.

Example 2 69.6 g. of trimethyl-ammonium-methyl-1,4-dioxane iodide are dissolved in 355 ml. of water. To this solution freshly prepared silver chloride (from 124 g. silver nitrate and hydrochloric acid) is added and the reaction mixture is shaken for seven hours at room temperature. The silver halides are filtered off and the filtrate is evaporated to dryness. The thus-obtained residue is recrystallized twice from an isopropanolzethyl acetate mixture and 29 g. of the trimethyl-ammonium-methyl-1,4-dioxane chloride of M.P. 273 (with decomposition) are obtained.

Instead of using silver chloride freshly prepared silver bromide may be used and the trimethyl-ammonium-1,4- dioxane bromide is obtained.

Example 3 of pyridine and 10 ml. of isopropanol is heated in a sealed tube to for four hours. Upon cooling the product separates as an oil which is washed once with a small volume of isopropanol, then dissolved in ethanol from which solution the product crystallizes on addition of ether. After recrystallization from isopropanol, 1.21 g. of pyridinium-(l)-methyl-1,4-dioxane iodide, M.P. 122- 123, are collected.

Example 4 A mixture of 2.3 g. of iodomethyl-l,4-dioxane, 1.1 g. of N-methyl-piperidine and 10 ml. of isopropanol are heated in a sealed tube for four hours to 140. On cooling, the product crystallizes from the reaction mixture and can be filtered off. After recrystallization from isopropanol 1.09 g. of Nmethyl-piperidinium-(l)-methyl- 1,4-dioxane iodide of M.P. 177-179 are obtained.

Example 5 A solution of 2.3 g. of iodomethyl-1,4-dioxane and 0.94 g. of N-methyl-pyrrolidine in 10 ml. of isopropanol is heated in a sealed tube for four hours at 140. The product crystallizes upon cooling and is recrystallized from a mixture of ethanol and ether. Yield 0.7 g. of N-methyl-pyrrolidinium-(l)methyl-1,4 dioxane iodide, M.P. ISO-131.

Example 6 An ethanolic solution of pyrrolidino-(1)-methyl-1,4- dioxane is refluxed with an excess of methyliodide over a period of three hours. The solution is evaporated to dryness and the residue recrystallized from a mixture of ethanolcether, yielding the N-methyl-pyrrolidinium-(1)- methyl-1,4-dioxane iodide which is identical with the product obtained according to the procedure given in Example 5.

The pyrrolidino-(l)-methyl-l,4-dioxane used as the starting material may be prepared as follows:

The solution of 4.6 g. of iodomethyl-l,4-dioxane and 4.76 g. of pyrrolidine' in 10 ml. of isopropanol is heated for four hours to 140. On cooling, the pyrrolidine hydroiodide crystallizes from the reaction mixture and is filtered off. The filtrate is concentrated under reduced pressure; the residue is dissolved in water and made alkaline. The base is extracted with ether and the residue distilled under reduced pressure. Unreacted pyrrolidine distills first; the second fraction of the distillation forms readily a hydrochloride, which is recrystallized from a mixture of tertiary butanolzethyl acetate, yielding the pyrrolidino-(l)-methyl-l,4-dioxane hydrochloride of the M.P. 133135. The base may be liberated by treatment with a dilute aqueous sodium hydroxide solution which is extracted with ether, from which ether solution the base may be isolated by evaporation of the ether.

Example 7 0.5 g. of 1,2,3,4-tetrahydroquinolino-(1)-methyl-1,4- dioxane in 5 ml. of ethanol are treated with 0.5 g. of methyliodide and the mixture refluxed for three hours, with adding twice an additional amount of 0.5 ml. of methyliodide. After evaporation of the solvent the residue is crystallized from a mixture of alcoholzethyl acetate and the N-methyl-1,2,3 ,4-tetrahydro-isoquinolinium-( 1)- methyl-1,4-dioxane iodide is recrystallized from a mixture of ethanolzisopropanol, M.P. 176l79 (with decomposition) The l,2,3,4 tetrahydroquinolino-(1)-methyl-1,4-dioxane used as starting material may be prepared as fol lows:

A solution of 3.45 g. of iodomethyl-1,4-dioxane and 4.2 g. of l,2,3,4-tetrahydroquinoline in 10 ml. of isopropanol is heated for four hours to in a sealed tube. The reaction mixture is then concentrated under reduced pressure and the residue is extracted twice with 35 ml. of ethyl acetate. The 1,2,3,4-tetrahydroquinoline hydroiodide formed remains undissolved. The ethyl acetate solution is evaporated to dryness and the residue is dissolved in dilute hydrochloric acid, which is washed twice With 35 ml. of ether. The remaining clear hydrochloric acid solution is made alkaline and the base extracted with chloroform. After removal of the chloroform the 1,2,3,4- tetrahydroquinolino-(l)-methyl 1,4-dioxane crystallizes, M.P. 63-66. Treatment of the base with hydrogen chloride in ethyl acetate gives the hydrochloride, M.P. 173-175.

Example 8 2.5 g. of 2-iodomethyl-5,6-dimethyl-1,4-dioxane and 15 ml. of a 22.8 percent solution of trimethylamine in ethanol are heated in a sealed tube for four hours at 80 100. After cooling, the reaction mixture is filtered and the filtrate concentrated to a syrup. On addition of ethyl acetate a crystalline product is obtained which is recrystallized from a mixture of isopropanolzethyl acetate. The 2-trimethyl-ammonium methyl-5,6-dimethyl-l,4-dioxane iodide has a M.P. of 172.5174.5.

The 2-iodomethyl-5,G-dimethyl-1,4-dioxane used as starting material is prepared as follows:

45 g. of butane-2,3-diol are dissolved in a mixture of 120 ml. of acetone, 35 ml. of water and a solution of 180 g. of sodium hydroxide flakes in 180 ml. of water. While stirring and refluxing gently a solution of 66.5 g. of. allyl bromide in 100 ml. of acetone is added dropwise over a period of two and one half hours. After the addition is completed, stirring and refluxing is continued for an additional hour, the acetone is then distilled off and 500 g. of ice, followed by 196 g. of concentrated sulfuric acid diluted with 300 ml. of water are added. The reaction mixture is extracted with ether and after evaporating the ether the residue is distilled under reduced pressure. The fraction boiling between 9093 at 50 mm./Hg, consisting of 2-allyloxy-3-hydroxy-butane, is collected.

A mixture of 13 g. of 2-allyloxy-3-hydroxy-butane and a solution of 30.28 g. of mercuric acetate in 100 ml. of water and 0.1 ml. of acetic acid is heated on the steam bath over a period of 45 minutes. After standing at room temperature overnight, the solution is filtered. Upon addition of a solution of 16.6 g. of potassium iodide in 25 ml. of water the 2-iodo-mercuri-methyl5,6-dimethyl-1,4-dioxane is precipitated as an oil. It is dissolved in 50 ml. of chloroform and combined with a solution of 19 g. of iodine in 450 ml. of chloroform. The reaction mixture is heated to boiling and then allowed to stand at room temperature for 18 hours. The mercuric iodide is filtered oif and the filtrate concentrated. The residue is distilled under reduced pressure (0.05 mm./ Hg) and the fraction boiling at 4752 consists of 2-iodomethyl-5,6-dimethyl-1,4-dioxane.

Example 9 To 0.66 g. of 2-iodomethyl-5,6-diphenyl-1,4-dioxane are added 30 ml. of a 20.8 percent solution of trimethylamine in ethanol and the mixture is heated for four hours at 100. On cooling the product crystallizes and after filtration is dissolved in ethanol. The 2-trimethyl-arnmonium-methyl-S,6-diphenyl-1,4-dioxane iodide crystallizes in needles upon addition of ethyl acetate, M.P. 193-195 The starting material for this preparation may be obtained as follows:

18.8 g. of hydrobenzoin are dissolved in 88 ml. of acetone and 22 ml. of water, to which solution 31.6 g. of sodium hydroxide in 32 ml. of water are added. The reaction mixture is heated to reflux with stirring. The solution of 12.1 g. of allyl bromide in 2-0 ml. of acetone is added dropwise over a period of two hours, stirring and refluxing are continued for one additional hour. 140 g. of ice and 30 ml. of water, followed by a solution of 17 ml. of concentrated sulfuric acid in 50 ml. of water are added. The product, the monoallyl ether of hydrobenzoin is-extracted with 160 ml. of isopropyl-ether and distilled under a reduced pressure of 4 m n/Hg and at a bath temperature of 180-200.

A mixture of 12.7 g. of the monoallyl ether of hydrobenzoin and 15.9 g. of mercuric acetate in 125 ml. of dioxane are stirred over a period of 1-6 hours. The unreacted mercuric acetate is then filtered off, and the filtrate concentrated under reduced pressure. A further quantity of mercuric acetate separates which is also filtered off. The filtrate is then concentrated to a syrup, which is dissolved in methanol. -On addition of 8.3 g. of potassium iodide in 20 ml. of water an oil precipitates which is taken up in chloroform. The chloroform solution is dried and evaporated to dryness, yielding 15.8 g. of 2-iodomercuri-methyl-S,6-diphenyl-1,4-dioxane. It is taken up in 25 m1. of chloroform, 6.9 g. of iodine in 150 ml. of chloroform are added, and the reaction mixture is heated to the boiling point and then allowed to stand at room temperature for two days. The mercuric iodide is filtered off and the filtrate is evaporated to dryness. The residue is extracted with hexane and on concentration the 2-iodomethyl-5,6-diphenyl-1,4-dioxane crystallizes from the hexane solution and is recrystallized from a mixture of ethyl acetatezethanol, M.P. 157-160".

Example 10 A mixture of 2.5 g. of 2-iodomethyl-6-methyl-l,4-dioxane and 18 ml. of 22.8 percent solution of trimethylamine in ethanol is heated in a sealed tube for four hours to to After cooling the reaction mixture is filtered and evaporated to dryness. The residue, 2-trimethyl-ammonium-methyl-6-methyl-1,4-dioxane iodide, is recrystallized from a mixture of ethanolzethyl acetate, M.P. 180-183.

The 2-iodomethyl-6-methyl-l,4-dioxane used as starting material may be prepared as follows:

A mixture of 11.6 g. of l-allyloxy-Z-propanol and 31.8 g. of mercuric acetate in 100 ml. of water and 0.1 ml. of acetic acid is heated on the steam bath for 45 minutes, then allowed to stand at room temperature for 16 hours. The reaction mixture is filtered and concentrated under reduced pressure. The remaining syrup is dissolved in water and made slightly alkaline with 2N sodium hydroxide. A solution of 16.6 g. of potassium iodide in 30 ml. of water is added and a yellow syrup precipitates. The latter is dissolved in chloroform and the solution is filtered and concentrated under reduced pressure. A solution of 12.3 g. of iodine in 400 ml. of chloroform is added to the syrup and the reaction mixture is refluxed gently over a period of two hours. After standing for two days at room temperature the mercuric iodide is filtered off and the filtrate concentrated under reduced pressure. The crude 2-iodomethyl-6-methyl-1,4-dioxane is distilled under reduced pressure (18 mm./ Hg), B.P.

Example 11 A mixture of 1.0 g. of iodomethy11,4-dioxane, 1.6 g. of quinoline and 5 ml. of isopropanol is heated in a sealed tube at over a period of two hours. After cooling the reaction mixture is filtered and evaporated to dryness, the residue, quinolinium-(1)-methyl-1,4-dioxane iodide, is recrystallized from isopropanol, M.P. 2 02-206".

Example 12 1.0 g. of iodomethyl-l,4-dioxane and 0.49 g. of triethylamine in 2 ml. of isopropanol are heated in a sealed tube at 115-120" over a period of 6 hours. After cooling the product crystallizes and the triethyl-ammoniummethyl 1,4 dioxane iodide is recrystallized from isopropanol, M.P. -178.

Example I 3 A mixture of 1.0 g. of dimethylamino-methyl-l,4-dioxane, 10 ml. of ethanol and 1.2 g. of ethyl iodide is refluxed for one hour. The reaction mixture is concentrated under reduced pressure and the residue, N,N-di- 9 hiethyl-N-ethyl-'ammonium-methyl-1,4-dioxaiie iodide, is recrystallized from a mixture of ethanolzethyl acetate, M.P. 152-155.

The starting material may be prepared as follows:

A mixture of 4.6 g. of iodomethyl-1,4-dioxane and 3.0 g. of dimethylamine (10 ml. of a 30 percent methanolic solution) in 10 ml. of isopropanol is heated for four hours at 150. The reaction mixture is concentrated, made alkaline with sodium hydroxide and then extracted with ether. The ether is removed and the residue is distilled under a reduced pressure of 20 mm./ Hg and at a bath temperature of 7176. 1.90 g. of dimethylaminomethyl-l,4-dioxane is obtained, which upon treatment with anhydrous hydrogen chloride in ethyl acetate solution yields the hydrochloride, which is recrystallized from a mixture of isopropanolzethyl acetate, M.P. 154-156".

Example 14 1.0 g. of dimethylamino-methyl-1,4-dioxane and 0.93 g. of allyl bromide in 10 ml. of ethanol are allowed to stand at room temperature for 18 hours. The reaction mixture is concentrated under reduced pressure and the residue dried over phosphorus pentoxide. On scratching, the very hygroscopic N,N-dimethyl-N-allyl-ammoniummethyl-1,4-dioxane bromide crystallizes, M.P. 91-94.

Example 15 A mixture of 1.0 g. of dimethy1amino-methyl-1,4- dioxane and 1.31 g. of n-propyliodide in 10 ml. of ethanol is refluxed for one hour. The reaction mixture is concentrated under reduced pressure and the N,N-dimeth-yl- N-propyl-ammonium-methyl-1,4-dioxane is crystallized on trituration with ethyl acetate, M.P. 110-113".

Example 16 A solution of dibenzylamino-methyl-l,4-dioxane in dimethylformamide is heated with an excess of methyliodide. The N-methyl-N,N-dibenzyl-ammonium-methyl- 1,4-dioxane iodide crystallizes on concentration of the solution.

The starting material dibenzyl-amino-methyl-l,4-dioxane may be prepared as follows:

5.00 g. of iodomethyl-1,4-dioxane and 13 g. of dibenzylamine in 40 ml. of methanol are heated in a sealed tube for four hours at 140. The solution is evaporated to dryness and fractional crystallization of the residue from methanol yields the dibenzylamino-methyl-l,4-dioxane, M.P. 6264.5. Treatment of the etheral solution of the amine with anhydrous hydrogen chloride yields the hydrochloride, M.P. 204208.

Example 17 A mixture of 94 g. of 2-iodomethyl-5-phenyl-1,4-dioxane and ml. of 22.8 percent solution of trimethylamine in ethanol is heated in a sealed tube for four hours to 90100. After cooling the crystalline product is filtered off and the Z-trimethyl-ammonium-methyl-5- phenyl-1,4-dioxane iodide is recrystallized from ethanol, M.P. 269-272.

The 2-iodomethyl-5-phenyl-l,4-dioxane used as starting material is prepared as follows:

To 5.34 g. of 2-allyloxy-2-phenyl-ethanol is added a. solution of 7.65 g. of mercuric acetate in 30 ml. of water and 0.03 ml. of acetic acid. The reaction mixture is heated on the steam bath for 45 minutes and then allowed to stand for 16 hours at room temperature. An oil separates which, after decanting the supernatant solution, is dissolved in methanol. A solution of 4.5 g. of potassium iodide in 5 ml. of water is added and an oil consisting of Z-iodomercuri-methyl-S-phenyl-1,4-di oxane precipitates. This oil is taken up in 50 ml. of chloroform, to which solution 4.85 g. of iodine in 125 ml. of chloroform are added. After heating to boiling the reaction mixture is allowed to stand for 16 hours at room temperature. The mercuric iodide is then filtered '10 off and the filtrate is evaporated to dryness. ciystal line residue, consisting of 2-iodomethyl-5-phenyl-l,4-di= oxane is recrystallized from a mixture of ethyl ac= tate:methanol, M.P. -108".

Example 18 Example 19 The quaternary ammonium-lower alkyl-1,4-dioxane compounds maybe used as active ingredients in medicinal preparations. Thus, the trimethyl-ammonium-methyl- 1,4#dioxane chloride described in Example 2 may, for example, be used in an 0.1 percent sterile and isotonic ophthalmic solution as follows:

Trimethyl-ammonium-methyl-1,4-dioxane chloride g 1.000 Sol. zephiran chloride 12.8% ml 1.560 Sodium acetate g 5.000 Solution acetic acid 10% ml 4.000 Sodium chloride g 4.500 Water for injection, to make up ml 1000.000

The above described solution is prepared as follows:

1.000 g. of trimethyl-ammonium-methyl-1,4-dioxane chloride is dissolved in 625 ml. of sterile water for injection. To this solution 1.560 ml. of zephiran chloride is added and the resulting solution thoroughly mixed. 4.000 ml. of the 10 percent aqueous solution of acetic acid prepared from fresh glacial acetic acid and sterile water for injection is added thereto. 5.000 g. of sodium acetate and 4.500 g. of sodium chloride are dissolved in 325 ml. of sterile water for injection. The solutions are combined and brought to a volume of 1000.000 ml. with sterile water for injection and the solution is filtered through a sterile, medium porosity, sintered glass filter. The filtrate is filtered again through a sterile millipore filter into a suitable sterile flask.

What is claimed is:

1. N,N,N trimethyl ammonium methyl 1,4-dioxane chloride.

2. N,N,N trimethyl ammonium methyl 1,4 dioxane iodide.

3. N,N,N trimethyl ammonium methyl 6 methyl-1,4-dioxane iodide.

4. N,N,N trimethyl ammonium methyl 5,6 di-- methyl-1,4-dioxane iodide.

5. N,N,N trimethyl ammonium methyl 5,6 di-- phenyl-1,4-di0xane iodide.

6. A compound of the formula:

in which the ammonium portion of the formula:v

7. A compound of the formula:

stands for an N,N,N-tri-lower alkyl-ammonium group, R for lower alkyl and X9 for the anion of a therapeutically suitable hydrohalic acid.

8. A compound of the formula in which each of the radicals R R and R represent lower alkyl, R, and R stand for members of the group consisting of hydrogen, lower alkyl and monocyclic aryl, and X for the anion of a therapeutically useful acid.

References Cited in the file of this patent UNITED STATES PATENTS 2,439,969 Forneau Apr. 20, 1948 2,445,393 Forneau July 20, 1948 2,606,909 Blicke Aug. 12, 1952 OTHER REFERENCES Richters Organic Chemistry, vol. 4, Heterocyclic Compounds, Elsevier, translated from 12th German ed., 1947, p. 4.

Bovet et al.: Medicaments du Systeme Nerveux Vegetatif (1948), p. 271.

Forneau: Soc. Chim de France, vol. 12, p. 848 (1945).

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,903,464 September 8, 1959 Lincoln Harvey Werner It is hereby certified that error appears in the printed specification of the abot e numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, lines 67 to 72, inclusive, the formula should appear as shown below instead of as in the patent:

R1 cash-R, x 0 I column 4, lines 54 and 55, for compounds. such read -compounds, such-; column 12, line 4, for and X for read -and X for-.

Signed and sealed this 10th day of May 1960.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofiicer. Oomz'esz'omer of Patents, 

1. N,N,N - TRIMETHYL - AMMONIUM - METHYL - 1,4-DIOXANE CHLORIDE. 